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At least 19 recordsLinked to original sources

Evidence for trans regulation of apoptosis in intertypic somatic cell hybrids.

The genetic components required for glucocorticoid induction of apoptosis were studied by using somatic cell hybridization. Intertypic whole-cell hybrids were generated by crossing the glucocorticoid-resistant rat liver cell line Fado-2 with the glucocorticoid-sensitive mouse thymoma cell line BW5147.3. Morphological and biochemical criteria were used to assess sensitivity or resistance to glucocorticoid-induced cell death. Both phenotypes were observed, and all of the hybrids retained a functional glucocorticoid receptor as judged by their abilities to induce the metallothionein gene in response to dexamethasone (Dex). Sensitivity to apoptosis did not correlate with morphological phenotype in that not all suspension cells were sensitive. The effect of glucocorticoids on the expression of apoptosis-linked genes was analyzed in a subset of Dex-sensitive and Dex-resistant hybrids. p53 and c-myc mRNAs were present in parental cells as well as sensitive and resistant hybrid cells, and their levels were not affected by glucocorticoid treatment. bcl-2 expression was restricted to the thymoma cell line and was also not affected by glucocorticoids. We did not detect any bcl-2 mRNA in the hepatoma cell line and the hybrids, suggesting that, as with most tissue-specific genes, bcl-2 is regulated in trans. Furthermore, while the majority of hybrids analyzed retained a full complement of mouse chromosomes, sensitive hybrids were missing some rat chromosomes (preferentially chromosomes 16 and 19), indicating that apoptosis is subject to trans repression. Resistant cells thus appear to repress the activity or synthesis of a nuclear factor that interacts with a glucocorticoid-dependent gene(s) to activate the cell death pathway.

Animals↗

The Polycomb and trithorax group proteins of Drosophila: trans-regulators of homeotic gene function.

The Polycomb and trithorax group genes encode trans-regulators of homeotic gene function in Drosophila. The Polycomb group genes encode transcriptional repressors, while the trithorax group proteins are positive factors required for homeotic gene function. Among the Polycomb group proteins, the POLYCOMB protein has been most extensively characterized. The POLYCOMB protein contains a chromodomain, a conserved domain found in a Drosophila protein with effects on position-effect variegation. Among the trithorax group proteins characterized, the BRAHMA protein appears to be a subunit of a protein complex conserved from yeast to man (the SNF/SWI complex) that modifies chromatin to facilitate the transcriptional activation by gene-specific DNA-binding proteins. The ZESTE protein may help to activate transcription by bringing distant cis-regulatory elements closer to promoter-bound proteins.

Animals↗

[Screening and identification of genes trans-regulated by a novel HbeAg interacting protein AK026018 with microarray assay].

BACKGROUND: To investigate the biological functions of a novel hepatitis B virus e antigen (HbeAg) interacting protein AK026018, and to use cDNA microarray technique to screen genes regulated by the protein. METHODS: The AK026018 coding DNA fragment was amplified by reverse transcription polymerase chain reaction (RT-PCR) technique from HepG2 cell. The expressive vector of pcDNA3.1-AK was constructed by routine molecular biological methods. The HepG2 cells were transfected with pcDNA3.1 and pcDNA3.1-AK, respectively by using lipofectamine. The total RNA was isolated and reverse transcribed. The cDNA of each sample was subjected to microarray screening with 8,464 cDNA probes and analyzed by bioinformatics. RESULTS: The expressive vector was constructed and confirmed by DNA sequencing analysis and restriction enzyme digestion. High quality mRNA and cDNA of transfected HepG2 cells had been prepared and successful microarray screening conducted. From the scanning results, there were 122 differential expression genes, of which 36 genes were down-regulated, and 16 genes were up-regulated. CONCLUSION: Microarray technique was successfully used to screen the genes trans-regulated by AK026018. The expression of AK026018 protein affects the expression spectrum of HepG2 cells.

Carrier Proteins↗

Theoretical investigation of the mechanism of cis-trans regulation for the allylnickel(II)-catalyzed 1,4 polymerization of butadiene.

In this Account we summarize the recent progress in the computational modeling of the transition-metal-catalyzed 1,3-diene polymerization. We present a comprehensive and theoretically well-founded view of the cis-trans regulation mechanism of the intriguing C-C coupling for the allylnickel(II)-catalyzed 1,4 polymerization of butadiene. The crucial elementary reactions of the entire polymerization process were theoretically explored for typical trans-1,4- and cis-1,4-regulating catalysts. As a result, the catalytic structure-activity relationships are deduced, which are responsible for opening that reaction channel which yields trans-1,4 and cis-1,4 polymer units.

Journal Article↗

Negative trans-regulation of T-cell antigen receptor/T3 complex mRNA expression in murine T-lymphoma somatic cell hybrids.

The antigen-specific T-cell receptor (TCR) is composed of variable antigen-recognition chains TCR-alpha and TCR-beta in noncovalent association with the invariant T3 multimer. The TCR-alpha and TCR-beta chains are encoded by gene segments that must be juxtaposed by rearrangement in order to be expressed. To examine whether mechanisms other than gene rearrangement might regulate TCR/T3 gene expression, somatic cell hybrids were formed among closely related murine SL12 T-lymphoma clones that differ in TCR/T3 mRNA levels. In hybrid cells formed between cell clones in which one parent is TCR-beta+ and the other is TCR-beta-, the resultant hybrid cells lack detectable TCR-beta transcripts. Since the protein synthesis inhibitor cycloheximide partially reverses TCR-beta repression in the hybrid cells, we postulate that a labile repressor protein is involved. The amount of mRNA encoding one of the T3 polypeptide chains, T3-delta, is also strongly negatively transregulated in the same hybrid cells in which TCR-beta mRNA expression is repressed. The negative trans-regulation of TCR-beta and T3-delta mRNA expression is relatively specific, since the levels of TCR-alpha mRNA and several thymocyte surface antigens are not repressed in somatic cell hybrids. Our results indicate that rearrangement of the TCR genes alone is not sufficient for TCR-beta expression and that trans-acting factors regulate the amounts of both TCR-beta and T3-delta mRNA in this system.

Animals↗

trans-repression of the mouse c-fos promoter: a novel mechanism of Fos-mediated trans-regulation.

Fos protein can trans-activate AP-1-dependent gene expression and trans-repress the c-fos promoter. Although we find that trans-repression is enhanced by coexpression of c-Jun, it does not require any of the AP-1 or ATF sites in the mouse c-fos promoter. A major target for repression is the serum response element (SRE). Fos mutants with an impaired leucine zipper are defective in trans-repression and transformation, suggesting that these functions involve the formation of Fos protein complexes. In contrast, mutations that abolish DNA binding of Fos enhance trans-repression but destroy the transforming potential of Fos. In addition, v-Fos protein efficiently transforms but is unable to trans-repress. These findings point to different mechanisms involved in trans-activation and trans-repression and suggest that trans-repression of the type described here is neither sufficient nor required for Fos-induced transformation.

Animals↗

["Cis" and "trans" regulator elements of transcription].

The 5'-flanking region of genes is involved in transcription regulaton. Multiple nucleotidic cis-acting sites are spread out over a region of 400 bp, (mostly) upstream of the start point. Examples are given with TATA box, GC box, CCAAT box and some octamers. Transcription factors recognize cis-acting sites and bind to them. Some are required for transcription initiation. Others affect (usually enhance) the rate of initiation. Trans-regulator proteins contain two domains. One is responsible for binding to DNA (as for instance: Zn fingers, Leu zipper, positive homeotic domain). The other one is responsible for activity on transcription (as for instance: rich in Gln, rich in Pro, acidic alpha-helix domain). Some technics used for determination of the site of transcription initiation and of protein fixation on DNA are briefly described. It is hoped that a better comprehension of transcription mechanisms will offer new possibilities of investigation for acting in some varieties of protein synthesis dysfunctionnements.

Genes, Regulator↗

Trans-regulation of epidermal growth factor receptor by lysophosphatidic acid and G protein-coupled receptors.

Lysophosphatidic acid (LPA) is known to induce protein tyrosine phosphorylation and has growth factor-like effects. In the last several years, the epidermal growth factor (EGF) receptor has been recognized as a protein tyrosine kinase that plays a central role in mediating LPA-induced tyrosine phosphorylation and Erk MAP kinase activation. In this article, we review recent progress in the study of trans-regulation of EGF receptor by LPA and G protein-coupled receptors (GPCR) and discuss the gap in our knowledge of the mechanism by which LPA induces EGF receptor activation.

Animals↗

Neu differentiation factor inhibits EGF binding. A model for trans-regulation within the ErbB family of receptor tyrosine kinases.

Neu differentiation factor (NDF, or heregulin) and epidermal growth factor (EGF) are structurally related proteins that bind to distinct members of the ErbB family of receptor tyrosine kinases. Here we show that NDF inhibits EGF binding in a cell type-specific manner. The inhibitory effect is distinct from previously characterized mechanisms that involve protein kinase C and receptor internalization because it occurred at 4 degrees C and displayed reversibility. The extent of inhibition correlated with both receptor saturation and affinity of different NDF isoforms, and it was abolished upon overexpression of either EGF receptor or ErbB-2. Binding kinetics and equilibrium analyses indicated that NDF reduced the affinity, rather than the number, of EGF receptors, through an acceleration of the rate of ligand dissociation and deceleration of the association rate. On the basis of co-immunoprecipitation of EGF and NDF receptors, we attribute the inhibitory effect to the formation of receptor heterodimers. According to this model, EGF binding to NDF-occupied heterodimers is partially blocked. This model of negative trans-regulation within the ErbB family is relevant to other subgroups of receptor tyrosine kinases and may have physiological implications.

Breast Neoplasms↗

Chromosomal assignment and trans regulation of the tyrosine aminotransferase structural gene in hepatoma hybrid cells.

The structural gene encoding liver-specific tyrosine aminotransferase (TAT; EC 2.6.1.5) was assigned to mouse chromosome 8 by screening a series of hybrid cell lines for retention of murine Tat-1 gene sequences by genomic Southern blotting. This assignment demonstrated that the Tat-1 structural gene was not syntenic with Tse-1, a chromosome 11-linked locus that negatively regulates TAT expression in trans (A. M. Killary and R. E. K. Fournier, Cell 38:523-534, 1984). We also showed that the fibroblast Tat-1 gene was systematically activated in hepatoma X fibroblast hybrids retaining fibroblast chromosomes 8 in the absence of chromosome 11 but was extinguished in cells retaining both fibroblast chromosomes. Thus, the TAT structural genes of both parental cell types were coordinately regulated in the intertypic hybrids, and the TAT phenotype of the cells was determined by the presence or absence of fibroblast Tse-1.

Animals↗

Saturating the eQTL map in Drosophila: Genome-wide patterns of cis and trans regulation of transcriptional variation in outbred populations.

Most genetic polymorphisms associated with complex traits are found in non-coding regions of the genome. Characterizing their effect presents a formidable challenge, and expression quantitative trait locus (eQTLs) mapping has been a key approach to do so. As comprehensive eQTL maps are available only for a few species, here we developed the Drosophila outbred synthetic population (Dros-OSP) and used it to characterize the landscape of transcriptional regulation in Drosophila melanogaster. We collected head and body transcriptomes and genomes from 1,286 outbred flies and mapped local and distant eQTLs for 98% of the genes. We characterized the network organization of the transcriptome across tissues and described the properties of local and distal eQTLs in terms of genetic diversity, heritability, connectivity, and pleiotropy. These results provide new insights into the genetic basis of transcriptional regulation in the fruit fly and offer a new mapping resource that will expand the possibilities currently available for the Drosophila community.

Animals↗

Trans-regulation of homeotic genes in Drosophila.

Homeotic genes of the Antennapedia and bithorax complexes control Drosophila development by encoding DNA-binding proteins that regulate the transcription of target genes. Because either the presence or absence of these DNA-binding proteins alters development, regulation of the spatial patterns of expression is crucial to normal development. Numerous gene products are required for properly regulated expression of Antennapedia and bithorax complex genes, but few (if any) are dedicated solely to the regulation of these genes. One of the pleiotropic activators of homeotic genes in Drosophila, the brahma gene, encodes a protein similar to a yeast protein that is required for transcriptional activation of multiple tightly regulated genes. Other components of this system may be conserved as well, suggesting that the biochemical basis for induced gene expression in single-celled organisms may have more in common with programmed developmental pathways in multicellular organisms than previously thought.

Animals↗

cis and trans regulation of tissue-specific transcription.

Analysis of both the cis-regulatory sequences which control globin gene switching as well as the trans-acting factors which bind to these sequences to elicit a differential, developmentally regulated response has lent insight into the general mechanisms responsible for tissue-specific gene regulation. We show here that the chicken adult beta-globin gene promoter sequences are intimately involved in competitive interaction with the beta/epsilon-globin enhancer to regulate differentially epsilon- versus beta-globin gene transcription. Secondly, we show that the family of GATA transcription factors directs gene regulation in a variety of discrete cell types, and describe potential cellular target genes for each member of the GATA factor family, as well as potential mechanisms whereby multiple GATA factors expressed in a single cell might be used to elicit differential transcriptional activities.

Animals↗

Enhancer-promoter communication at the yellow gene of Drosophila melanogaster: diverse promoters participate in and regulate trans interactions.

The many reports of trans interactions between homologous as well as nonhomologous loci in a wide variety of organisms argue that such interactions play an important role in gene regulation. The yellow locus of Drosophila is especially useful for investigating the mechanisms of trans interactions due to its ability to support transvection and the relative ease with which it can be altered by targeted gene replacement. In this study, we exploit these aspects of yellow to further our understanding of cis as well as trans forms of enhancer-promoter communication. Through the analysis of yellow alleles whose promoters have been replaced with wild-type or altered promoters from other genes, we show that mutation of single core promoter elements of two of the three heterologous promoters tested can influence whether yellow enhancers act in cis or in trans. This finding parallels observations of the yellow promoter, suggesting that the manner in which trans interactions are controlled by core promoter elements describes a general mechanism. We further demonstrate that heterologous promoters themselves can be activated in trans as well as participate in pairing-mediated insulator bypass. These results highlight the potential of diverse promoters to partake in many forms of trans interactions.

Animals↗

Trans-regulated silencing and reactivation of TP53 tumor suppressor gene in malignant transformation and its reversion.

Despite growing interest in the methylation-mediated silencing of tumor suppressor genes in the neoplastic process, its signaling mechanism remains largely unknown. Here we show in a cultured murine cell line system that the silencing and reactivation of tumor suppressor gene TP53 were reversibly controlled by a trans-acting regulatory mechanism. The gene product p53, which was constitutively expressed and activated upon X-ray irradiation in non-malignant parental cell line, was undetectable in its X-ray-induced malignant transformants, while they retained a wild-type TP53. The silencing was cancelled by transferring a human chromosome 11 and the expression of p53 was restored. The non-malignant revertants thus obtained were again susceptible to transformation by X-irradiation, giving rise to re-transformants, in which p53 was again repressed while the human chromosome 11 retained the ability to turn on TP53 when it was transferred into other malignant clone. The silent TP53 could be reactivated by treatment with the demethylating agent 5-azadeoxycytidine. These observations indicate the presence of a trans-acting signaling mechanism in the methylation-mediated regulation of TP53 expression which is associated with the acquisition of malignancy.

Animals↗

Trans-regulation of thoracic homeotic selector genes of the Antennapedia and bithorax complexes by the trithorax group genes: absent, small, and homeotic discs 1 and 2.

Genes of the trithorax group appear to be required for the maintenance of expression of the homeotic selector genes of the Antennapedia and bithorax complexes. According to genetic criteria, the Drosophila melanogaster genes absent, small, or homeotic discs 1 and 2 (ash1 and ash2) are members of the trithorax group. In this paper we examine the consequences of ash1 and ash2 mutations on the expression of homeotic selector genes in imaginal discs. The results of these experiments demonstrates that both ash1 and ash2 are trans-regulatory elements of homeotic selector gene regulation. Hypomorphic ash1 mutations cause variegated expression of Antennapedia, Sex combs reduced, Ultrabithorax, and engrailed. Complete loss of ash2 activity causes the loss of expression of Sex combs reduced in first leg imaginal discs, loss of expression of Ultrabithorax in third leg discs, and a late-patterned loss of expression of Ultrabithorax within haltere discs, yet has no effect on engrailed or Antennapedia expression. These results suggest that the range and action of trithorax group genes is varied and complex and argue against any model in which all of the products of the trithorax group act together in a single mechanism or complex.

Animals↗

A genetic analysis of extinction: trans-regulation of 16 liver-specific genes in hepatoma-fibroblast hybrid cells.

Hybrid cells formed by fusing different cell types generally fail to express the tissue-specific products of either parent, a phenomenon termed extinction. We have investigated the generality of this effect by assaying hepatoma-fibroblast hybrids for expression of 16 different liver-specific mRNAs. Fourteen of the mRNAs failed to accumulate in karyotypically complete hybrid clones, and quantitative measurements indicated that steady-state mRNA levels were depressed by a factor of at least 500-1000. However, all 14 liver-specific mRNAs were reexpressed in the hybrids following fibroblast chromosome loss. These data indicate that expression of whole sets of tissue-specific genes is affected in trans in intertypic hybrids and suggest that negative regulation of heterologous functions may be common form of gene control.

Alcohol Dehydrogenase↗

Human immunodeficiency virus type 1 rev protein as a negative trans-regulator.

Even though the rev gene of the human immunodeficiency virus type 1 (HIV-1) is essential for viral replication, high levels of rev also downregulate viral gene expression. As the degree of rev protein expression exceeds expression of wild-type virus, a gradient of decreasing viral mRNA synthesis becomes evident. The target sequence for this downregulation resides outside of trans-activating region (TAR) and upstream from the enhancer sequences in the long terminal repeat (LTR), suggesting that regulation is at a transcriptional level.

Cell Line↗